DESCRIPTION (Applicant's Description) Pancreatic cancer contributes 5 percent of the total cancer death in this country. It is a deadly disease with little known about the etiology. The most consistently identified epidemiological risk factor for pancreatic cancer is cigarette smoking. Dietary and industrial carcinogens have also been suspected to be involved. Among all human cancers, pancreatic cancer has the highest frequency (85 percent) of K-ras mutation and this event occurs in the early stage of tumor development. Half of these mutations are C to A transition, a point mutation induced by nitrosamines and other alkylating agents in experimental animals. Nitrosamines are potent inducers of pancreatic tumors in hamsters but not in rats. Variation in carcinogen metabolizing enzymes between the two species has been credited for the difference in their susceptibility to the exposure. Based on this information, we propose two hypotheses: 1) Exposure to nitrosamines and other alkylating agents leads to formation of DNA alkylation products which cause K- ras mutations; 2) individuals with increased susceptibility to such exposure are at greater risk for pancreatic cancer than are non-susceptible individuals. To test these hypotheses, we will take a molecular epidemiological approach with a case-control study. 100 newly diagnosed pancreatic cancer patients will be matched with 100 non-cancer controls by age, sex, ethnicity and smoking. We will measure carcinogen exposure by a detailed questionnaire collecting information on occupation, smoking, alcohol consumption and dietary history. We will determine genetic polymorphisms of the carcinogen metabolizing enzymes, cytochrome P450 lAl and 2E1, N-acetyl transferase 1 and 2, and glutathione S transferase. We will measure DNA repair capacity by applying two carcinogen-induced DNA damage assays. We will detect DNA damage derived from exposure to PAH and alkylating agents in the target tissues of cases. The DNA damage profiles will be analyzed in relation to K-ras mutation profiles in the tumors. Finally, the epidemiological data will be analyzed along with the biomarker data to examine the gene and environmental interactions. The long-term goal of our research is to identify the genetic and environmental factors that influence the risk of developing pancreatic cancer, therefore novel strategies can be developed for prevention and early detection of the disease. This pilot study is intended to set the stage for a large scale of investigation in the near future.